Monoclonal immunoglobulins displaying cryoglobulin behavior are associated with a variety of lymphoproliferative disorders and both chronic and acute infectious disease. Depending on the absolute concentration and relative thermal sensitivity of these proteins, a range of cutaneous, neurologic, renal and vasomotor complications can develop. The proposed studies are directed at elucidating the molecular basis for cryoglobulin behavior and will be directed at both monoclonal and mixed (monoclonal IgM component) cryoimmunoglobulins. Included in these investigations of the monoclonal cryoimmunoglobulins will be studies directed at characterizing the relative hydrophobic properties of these proteins using analytical hydrophobic chromatography and two-phase partitioning techniques. Tertiary structure properties will be explored utilizing solvent perturbation difference spectroscopy. In these and the applicable studies indicated below, studies will be carried out as a function of temperature in order to relate the findings to the phase separation occurring upon reduction of temperature with these immunoglobulins. The studies will continue to address the relationship of cryoglobulin behavior to general aspects of polypeptide solubility. Structural features such as atypical anionic detergent-binding properties found to be common to genetically (heavy and light chain subgroups) dissimilar cryoimmunoglobulins will be examined in order to determine the origins of the effects in the three dimensional structure of these proteins. A primary structure basis for cryoglobulinemia will continue to be investigated in several molecules using automated N-terminal sequencing techniques. Studies will be initiated in order to characterize the relationship of Fc binding to cryoprecipitation of mixed cryoglobulins. The intra-Fc binding site for the IgM component will be explored by Fc subfragmentation techniques, and a role for an induced conformational change on Fc binding will be sought using near or far ultraviolet circular dichrosim. It is anticipated that these investigations will serve to further our understanding of the molecular pathology of cryoglobulinemia.